Defects in EMSY Gene Spur Ovarian Cancer Growth

BRCA1/2 mutations have long been attributed to the development ovarian cancer; however, women with healthy BRCA genes are still receiving a cancer diagnosis.

A study was conducted to investigate whether changes in the EMSY gene attributed to cancer cell growth in patients with ovarian cancer who have healthy BRCA genes.

In the study, the full-length EMSY gene was overexpressed, resulting in suppression of homologous recombination, much like BRCA2. However, these changes in EMSY contribute to cancer growth independently as there is no direct interaction with BRCA2, says senior study author Douglas A. Levine, MD.

Levine, who is director of the Division of Gynecologic Oncology at NYU Langone Medical Center and Perlmutter Cancer Center, says that with this study, therapies can now be designed to target the specific activity of these EMSY cells. For example, PARP inhibitors are being explored as a potential treatment option for EMSY-driven cancer, as they have been shown to be effective in patients with mutated BRCA genes.

In an interview with OncLive, Levine discussed the relationship between EMSY and BRCA, the potential to target EMSY amplified tumors with PARP inhibitors, and the future of ovarian cancer treatment.

OncLive: Could you provide a brief overview of the study?

Levine: The EMSY gene was discovered probably 15 years ago and it was thought to interact with BRCA2 and suppress it as well as sort of mimic the function of BRCA2. In this study, we wanted to see if it truly has the biological effects that BRCA2 suppression would have.

We discovered, through some of our prior work in ovarian cancer, that EMSY is amplified in more than 10% of cases, which is important to know in treating the disease. First, we overexpressed the full length of the gene—which no one has been able to do before. By overexpressing the full-length gene, we are able to show that it does indeed suppress DNA repair—a specific type of DNA repair called homologous recombination. That is the type of repair in which BRCA2 also causes suppression; this is called homologous recombination deficiency.

Although it did suppress that type of DNA repair to a lesser extent than BRCA2 does by itself, our second question was, “Does the protein directly interact with BRCA2?” This has been reported in at least 1 study. We demonstrated that there was no direct interaction between EMSY and BRCA2.

Once we showed that there was no direct interaction, our next question was, “How does EMSY suppress homologous recombination if there is no direct interaction?” By reviewing the literature and having some internal discussions, we started to look for some various binding sites and we found a phosphorylation site at a new location in the protein. When this binding side was mutated, it could no longer carry out the function of suppression of DNA repair.

In short, we identified routes to overexpress the full-length protein, showed that it doesn’t directly interact with BRCA2, that it affects homologous recombination, and that a specific phosphoric site that we identified mediates it.

As of now, is there an effective way to identify these defective EMSY genes?

It’s an amplification of a gene; it’s kind of a copy number alteration and so it’s relatively easy to do this. We haven't done it on individual clinical specimens; however, there are several standard ways to look for amplified genes that we do for various other genes. We just have to use the right antibody and we could stain tissues using fluorescent markers, but we did not do that for this study because we were working in cell lines.

We had done the discovery in human tissue using whole-genome approaches, which was done prior to this report becoming the basis for our work. In a clinical specimen, you would do some sort of fluorescent-antibody approach or now we can do droplet pathological complete response, as well. It would not be difficult, but we have not done that for clinical purposes yet.

Could you speak to the successes of PARP inhibition both in this study and in ovarian cancer overall?

For 10 years, we have known that tumors that are defective in homologous recombination are very sensitive to DNA damage agents, such as platinum-based chemotherapy. More importantly, they are exquisitely sensitive to PARP inhibitors. Our next step in the process is to figure out if EMSY amplification does indeed result in sensitivity to PARP inhibitors.